Insulin is a kind of hormones which is produces by β-cells in Langerhans islets of the pancreas. Insulin acts on lipid metabolism and protein metabolism as well as sugar metabolism via insulin receptors which are present in target tissues of insulin such as skeletal muscles, liver, and fats, and plays an important role in maintaining homeostasis of living bodies. Examples of the effects of insulin on respective target tissues include promotion of incorporation of glucose from blood into muscle cells and adipocytes, promotion of glycogen production in liver and muscle tissues, inhibition of gluconeogenesis in liver, promotion of glucose consumption and fatty acid synthesis in adipocytes, and inhibition of decomposition of lipids.
The insulin resistance means a state where the cells, organs, or individuals require larger amounts of insulin than those typically required in order to obtain the respective effects of insulin, that is, an insulin effect incompetent state where sensitivity to insulin is reduced. From the results of past epidemiologic investigations, hypertension, diabetes, hyperlipidemia (hypertriglyceridemia and hypo-HDL-cholesterolemia), obesity, and the like are considered as pathosis caused by the insulin resistance. The insulin resistance causes insufficient effects of insulin on the sugar metabolism, which results in compensatory hyperinsulinemia for maintaining blood sugar level, whereby hyperglycemia and glucose intolerance occur and diabetes is promoted by exhaustion of pancreatic β-cells. In addition, the hyperinsulinemia enhances activation of sympathetic nerves and accelerates sodium absorption of kidney to cause hypertension, and also induces postprandial hyperlipidemia and hyperuricemia, an increase in plasminogen activator inhibitor-1 (PAI-1), and the like.
Meanwhile, the insulin resistance induces abnormal lipid metabolism caused by the insufficient effects of insulin, and free fatty acid (FFA) released from adipocytes increases in liver to accelerate synthesis of triglyceride (TG) therein, resulting in hypertriglyceridemia. In addition, activity of lipoprotein lipase (LPL) generally having high insulin sensitivity is reduced in the insulin resistant state, so decomposition of TG reduces and the hypertriglyceridemia is additionally aggravated. Further, progression of diabetes causes onset of complications such as retinopathy, nephropathy, and gangrene caused by angiopathy so that myocardial infarction and cerebral infarction that are arterioscleotic diseases proceed, and hypertension promotes cardiovascular diseases. As described above, the insulin resistance is considered to be significantly involved in aggravation of complication of pathosis (Non-patent Document 1).
In recent years, analysis of organ-specific gene expression has been conducted. As a result, it was found that various physiologically active substances are secreted from fat tissues, and the fat tissues thus have been recognized to be, not only energy storage tissues, but also the largest endocrine organ in a living body. Endocrine factors derived from the fat tissues have a generic name “adipocytokines” and play important roles in maintenance of homeostasis in metabolism. It is considered that an excessive or a too small amount of adipocytokines are produced and secreted in a case of obesity, that is, a state where fats are accumulated, and the balance of the adipocytokines is disrupted, resulting in insulin resistance.
The adipocytokines are classified into two groups: one that enhances insulin sensitivity; and one that elicits insulin resistance. Representative examples of the former group include adiponectin, leptin, and AMP-dependent protein kinase (AMPK) and the like. In particular, adiponectin has been reported to have an effect of canceling insulin resistance and an effect of inhibiting gluconeogenesis in liver (Non-patent Document 2).
Meanwhile, examples of the adipocytokines that elicit insulin resistance include, in addition to the aforementioned FFA and PAI-1, tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1) that is a kind of inflammatory chemokine, and resistin. In particular, TNF-α has been reported to have an effect of inhibiting tyrosine phosphorylation of an insulin receptor and IRS1 (insulin receptor substrate 1) in the insulin signal transduction mechanism so that the effect of insulin is attenuated, whereby insulin resistance is elicited. In addition, there is a report that, in the insulin resistant state, the MCP-1 level in a living body increases and mRNA of GLUT4 (glucose transporter-4) that is a glucose-transporting carrier, PPARγ (peroxisome proliferator-activated receptor γ) that is an intranuclear receptor, β3AR (β3-adrenergic receptor) that is a kind of β catecholamine receptor of an adipocyte, and aP2 (adipocyte fatty-acid-binding protein 2) that is a fatty acid-binding protein reduces. Thus, MCP-1 is considered to be a causative agent that reduces insulin sensitivity (Non-patent Documents 3, 4, and 5).
As agents for improving insulin resistance, biguanide agents that inhibit gluconeogenesis mainly in liver and thiazolidine derivatives for improving insulin sensitivity of muscles and fat tissues have been developed. Those agents have already been permitted as diabetic medicines, and also used for treatment of arterioscloerotic disease. The thiazolidine derivatives typified by troglitazone and pioglitazone are each considered to act as a ligand for a peroxisome proliferator-activated receptor (PPAR) that is an intranuclear receptor-type transcription factor to promote differentiation of adipocytes, thereby improving insulin resistance.
In addition, an agent for improving insulin resistance containing adiponectin or their genes as an active ingredient (Patent Document 1), a preventive and/or therapeutic agent for diseases due to insulin resistance, which contains as an active ingredient a substance having affinity to bombesin receptor subtype 3 (BRS-3) (Patent Document 2), a free fatty acid (FFA) reducing agent containing as an active ingredient a pyrrole derivative (Patent Document 3) and the like have been disclosed as the agents for improving insulin resistance. Further, a composition for improving insulin resistance containing, as an active ingredient, acetic acid and an ion or salt thereof (Patent Document 4), an agent for improving insulin resistance containing a fatty oil which contains particular diglyceride and/or monoglyceride (Patent Document 5) and the like have been disclosed as the agents containing as an active ingredient a substance derived from food or drink.
Plant sterols such as β-sitosterol, campesterol, stigmasterol have been known to have a reducing effect on blood cholesterol by inhibition of absorption of the cholesterol, and practical use thereof has been attempted by adding them as a fat composition to edible oil. In addition, there are disclosed an anti-obesity agent and a lipid metabolism-improving agent containing as an active ingredient a cholestenone compound which is synthesized by using as a starting material the plant sterols such as β-sitosterol and campesterol (Patent Documents 6 to 8, and Non-patent Document 6).
Further, there is disclosed an agent for promoting adiponectin secretion containing: an extract derived from at least one of rice bran, shimeji mushroom, chrysanthemum, rye, white birch, and Spanish Jasmine (Alpinia zerumber), and cycloartane type triterpene or cycloartenol and/or (24S)-24,25-dihydroxycycloartanol which are derivatives thereof (Patent Document 9).
The plants belonging to the genus Aloe of Liliaceae are a group of plants including Aloe vera (Aloe barbadensis Miller), Aloe arborescens (Aloe arborescens Miller var. natalensis Berger), and the like, and have been known to have various effects from experience. For example, there are disclosed an immunodepression-improving agent containing a butanol fraction of an aloe extract or aloin (Patent Document 10), agents related to improving blood glucose level (Patent Documents 11 to 14), and a preventive and improving agent for obesity (Patent Document 15) and the like, but the improving action on insulin resistance of the plants belonging to the genus Aloe has not been reported.    [Patent Document 1] International Publication NO. WO 2003/63894    [Patent Document 2] Japanese Patent Laid-open No. 10-298100    [Patent Document 3] Japanese Patent Laid-open No. 08-12573    [Patent Document 4] Japanese Patent Laid-open No. 2002-193797    [Patent Document 5] Japanese Patent Laid-open No. 2001-247473    [Patent Document 6] Japanese Patent Laid-open No. 07-165587    [Patent Document 7] Japanese Patent Laid-open No. 11-193296    [Patent Document 8] Japanese Patent Laid-open No. 2001-240544    [Patent Document 9] Japanese Patent Laid-open No. 2005-68132    [Patent Document 10] Japanese Patent Laid-open No. 08-208495    [Patent Document 11] Japanese Patent Laid-open No. 60-214741    [Patent Document 12] Japanese Patent Laid-open No. 2003-286185    [Patent Document 13] U.S. Pat. No. 4,598,069    [Patent Document 14] U.S. Patent Application Publication No. 2003/0207818    [Patent Document 15] Japanese Patent Laid-open No. 2000-319190    [Non-patent Document 1] Insulin resistance and lifestyle-related diseases, Ed. Kazuaki Shimamoto, Shindan to Chiryo Company, 2003, pp. 1-5    [Non-patent Document 2] Adiposcience, 1(3), 2004, pp. 247-257    [Non-patent Document 3] Proceedings of the National Academy of Sciences, vol. 100, 2003, pp. 7265-7270    [Non-patent Document 4] Nature, vol. 389, 1997, pp. 610-614    [Non-patent Document 5] The Netherlands Journal of Medicine, 6(6), 2003, pp. 194-212    [Non-patent Document 6] Hormone Metabolism Research, vol. 37, 2005, pp. 79-83